Various types of infectious diseases, such as those caused by bacteria, viruses or fungi, have been known. As a therapeutic method for infectious diseases caused by bacteria, administration of antibiotics has been carried out. However, such administration of antibiotics has been problematic in terms of the emergence of microbes resistant to antibiotics. It has also caused in-hospital infection of such resistant microbes. In addition, administration of antibiotics has also been problematic in terms of opportunistic infection, which is common in immune-compromised patients who are infected with HIV, who are under treatment with anticancer agents, and who are elder people or children, etc.
Moreover, in the case of infection with enteropathogenic Escherichia coli such as O-157 or Shigella dysenteriae, verotoxin is generated in vivo, and severe symptoms such as combination with hemolytic uremic syndrome may occur particularly in the case of elder people or children with compromised immune systems. To such infectious diseases, antibiotics may be administered in some cases. However, it has been pointed out that administration of antibiotics may cause to kill bacteria, and as a result, toxin existing in the bacteria may be released to outside of the bacteria at once, so that the condition may be deteriorated. On the other hand, in the case of highly contagious infection diseases, such as O-157, which are transmissible only by ingestion of several hundreds of to several thousands of bacteria, there may be cases in which administration of antibiotics should be selected to prevent secondary infection. With regard to other therapeutic methods, since approximately 10% of all the O-157 infection cases may combine with hemolytic uremic syndrome, plasma exchange, dialysis therapy, and the like are carried out on such O-157 infection cases. These are all therapeutic methods which may impose an undue burden on patients.
Furthermore, as a method for coping with toxin generated by bacteria, symptomatic therapy is mainly carried out. Other methods include the use of a toxin adsorbent, the use of an antibody against such toxin, and the like. Such adsorption methods involving the use of activated carbon or the like may cause side effects such as constipation. Further, the use of an antibody is inconvenient in that an antibody must be developed against each type of toxin.
Thus, a method for treating infectious disease caused by such pathogenic bacteria or a method for suppressing the onset of such infectious disease has been searched for. Recently, it has been attempted to treat or prevent infectious diseases by enhancing a patient's own immune system without administering antibiotics.
Various compounds have been studied in order to find out substances for enhancing the patient's own immune system. As examples of ingredients obtained from natural products, trehalose dimycolate (TDM) and trehalose dicorynomycolate (TDCM), which are diester compounds of trehalose, have been known. TDM has been discovered as a glycolipid existing on the cell cortex of Mycobacterium tuberculosis, and it has been known to exhibit immunostimulatory activity and anticancer activity. Moreover, TDCM has been isolated, as a homolog having fewer carbon atoms than those of TDM, from related Corynebacterium spp. It has been revealed that both TDCM and a stereoisomer thereof exhibit immunostimulatory activity and anticancer activity.
However, TDM and TDCM are highly toxic, and thus, they cannot be used as pharmaceutical products. Accordingly, in order to use TDM and TDCM as pharmaceutical products, it has been necessary to synthesize compounds with reduced toxicity, while maintaining or enhancing their activity.
Hence, a trehalose 6,6′-diester compound, which is a trehalose fatty acid ester composition, has been synthesized as a TDM derivative. Various tests, such as a toxicity test and a macrophage activating test, have been performed on the trehalose 6,6′-diester compound (see Non Patent Literature 1). In this publication, the presence or absence of a β-hydroxyl group, compounds having 30, 32 or 48 carbon atoms as a length of the alkyl portion of a lipid, compounds in which the ester bond between a sugar and a lipid has been replaced by an amide bond, etc. have been studied. In terms of toxicity, this publication describes that an ester bond and a long chain fatty acid greatly contribute to toxicity. This publication describes a compound having 30 carbon atoms as a length of a side chain fatty acid portion. However, in order to obtain a compound having high activity and low toxicity, the binding manner of a sugar and a side chain, the presence or absence of a substituent for a side chain fatty acid, the length of an alkyl group constituting such a side chain fatty acid, and the like have not been comprehensively studied and have not been optimized. Tests have been just sporadically carried out on several compounds as described above. Even with regard to immunostimulatory action, the contents thereof have not been studied in detail.
On the other hand, with regard to a TDM derivative, the present inventors have synthesized a TDM derivative having an ester bond or an amide bond, in which the β-hydroxyl group has been replaced by a hydrogen atom or a methoxy group (see Patent Literature 1). However, the derivative described in this publication has a comparatively short alkyl portion of fatty acid (approximately 7 carbon atoms). With regard to its activity, only activity as an adenosine A3 receptor antagonist was measured.
The present inventors have succeeded in substituting the hydroxyl group of TDCM with a hydrogen atom, so that it could not be an asymmetric carbon atom, as well as in synthesizing an amide derivative of TDCM, in which the ester bond has been replaced by an amide bond. The inventors have then confirmed that these amide derivatives have immunostimulatory action (see Patent Literature 2). However, thereafter, it has been found that these amide derivatives have action to induce cancer, and as a result, it could not help giving up the use of the amide derivatives as pharmaceutical compounds.
Therefore, a sufficiently effective and highly safe method for treating various symptoms caused by pathogenic bacteria or suppressing the onset of such symptoms, using such a TDM or TDCM derivative, has not yet been established. Thus, it has been desired to develop an effective and safe method for treating the symptoms caused by pathogenic bacteria or suppressing the onset of the symptoms.